A novel TP53 somatic mutation involved in the pathogenesis of pediatric choroid plexus carcinoma.

BACKGROUND: Choroid plexus carcinoma (CPC) is an uncommon, aggressive, malignant, central nervous system neoplasm that typically occurs in children, presenting with the signs and symptoms of intracranial hypertension and cerebrospinal fluid obstruction. CASE REPORT: We report the case of a 2.5-year-old girl with CPC. The tumor was subtotally removed by microsurgery, followed by gamma knife radiosurgery for the residual lesion. H&E staining indicated that this was a rare case of CPC. Neuropathological studies, assayed by immunohistochemical staining, showed that the tumor sample was positive to antibodies against S-100, CgA, AE1/AE3 (cytokeratin), Ki-67, INI1 and TP53, and was negative to antibodies against Nestin, GFAP, CD133, EMA and AFP. Moreover, stainings for transthyretin and vimentin were focally positive. Interestingly, direct DNA sequencing of the paraffin-embedded tumor sample identified a novel R248Q mutation in the TP53 gene. In contrast to previous reports suggesting that TP53 germline mutations were associated with the pathogenesis of CPC, here we provide a rare case of CPC with TP53 somatic mutation, as evidence that the peritumoral tissue possesses the non-mutant TP53 allele. CONCLUSIONS: Our finding suggests that TP53 somatic mutations, in addition to its germline mutations, may also be involved in the pathogenesis of pediatric CPC.

Expression and cellular distribution of vascular endothelial growth factor-C system in cortical tubers of the tuberous sclerosis complex.

Cortical tubers are malformations of cortical development in patients with tuberous sclerosis complex (TSC), and highly associated with pediatric intractable epilepsy. Recent evidence has shown that signaling mediated through vascular endothelial growth factor-C (VEGF-C) and its receptors, VEGFR-2 and VEGFR-3, has direct effects on both neurons and glial cells. To understand the potential role of VEGF-C system in the pathogenesis of cortical tubers, we investigated the expression patterns of VEGF-C signaling in cortical tubers compared with age-matched normal control cortex (CTX). We found that VEGF-C, VEGFR-2 and VEGFR-3 were clearly upregulated in tubers at both the mRNA and protein levels, compared with CTX. The in situ hybridization and immunostaining results demonstrated that VEGF-C, VEGFR-2 and VEGFR-3 were highly expressed in dysplastic neurons (DNs), giant cells (GCs) and reactive astrocytes within tubers. Most DNs/GCs expressing VEGF-C and its receptors co-labeled with neuronal rather than astrocytic markers, suggesting a neuronal lineage. In addition, protein levels of Akt-1, p-Bad and ERK1/2, the important downstream factors of the VEGF-C pathway, were significantly increased in cortical tubers, indicating involvement of VEGF-C-dependent prosurvival signaling in cortical tubers. Taken together, our results suggest a putative role for the VEGF-C signaling pathway in the pathogenesis of cortical tubers.

SVZa neural stem cells differentiate into distinct lineages in response to BMP4.

Neural stem cells (NSCs) reside in the anterior portion of the forebrain subventricular zone (SVZa) and generate the progenitors which will differentiate into neurons, and via a tangential migratory pathway, known as the rostral migratory stream (RMS), migrate to the olfactory bulbs (OB). Bone morphogenetic proteins (BMPs) play significant roles in neural development at different stages and locations, but their roles have not been determined in the SVZa. To explore possible roles of BMPs in SVZa NSCs, BMP4 at various concentrations were tested for their capacity to induce SVZa NSCs. The expression of BMP4 was also examined in living cells using a reportor vector, in which the BMP4 promotor was conjugated with red fluorescent protein (RFP). In the meantime, the differentiation of SVZa NSCs was dynamically monitored by using reportor vectors of the Nestin enhancer and the promoters of TH and GFAP. In the OB, high expression of BMP4 was found using both promoter activity analysis and in situ hybridization. However, low BMP4 expression was found in the RMS and only moderate expression of BMP4 was displayed in the SVZa. The results also demonstrated that low concentrations (1-5 ng/ml) of BMP4 promoted the proliferation of SVZa NSCs but high concentrations (10-100 ng/ml) of BMP4 inhibited this proliferation. BMP4 enhanced neuron commitment before 4 days but inhibited it after 4 days. As the antagonist of BMP4, Noggin almost completely blocked all these BMP4 responses. Thus, our findings indicate that BMP4 promotes the exit from the cell cycle and triggers the differentiation of neuron progenitors in the OB. BMP4 also promotes the proliferation of the committed neuron progenitors in the RMS, but in the SVZa, BMP4 may facilitate the commitment of NSCs into astrocytes.